Insect repellents



Patented July 29, 1952 UNITED STATES "PATENT. OFFICE.)

2,605,201 11 INSECT REPELLENTS I v, Nathan L. Drake, College Hcights,Md.,fCharles 7' M. Eaker, Afiton, M0,,"and Wilbur J-.- Sh'enk,

Cleveland, Ohio, assignors to the United States I of America asrepresented by the Secretaryof the Army N Drawing. Application'jgtnuary11,l 1 9 49',

Serial N0. 70,.39 '7 ye Claims. (olis veabr This invention relates toinsect repellent We have found that the application of certain esters ofthe general formula G.Y.R

wherein n is 4 or 5, Y is --COO-- or -CH2COO, and R is an alicyclic' oran unsubstituted or substituted aliphatic radical preferably'having atleast 3 carbon atoms, when applied to the human skin or to afabric,effectively repels insects, particularly A'des aegypti and Anophelesquadrimaculatus.

Thus, suitable acids whose esters are. insect repellent, are1-hydroxyecyc1opentanecarboxylic acid, .1-hydroxy-cyclopentaneaceticacid, l-hydroxy-cyclohexanecarboxylic' acid, and1-hydroxy-cyclohexaneacetic acid; among suitable alcohol radicals of ouresters are for example alkyl such as ethyl, 'propyl,. butyl, iso-amyl;ketonyl such as acetonyl; ethoxyalkyl' such as ethoxyethyl; andcycloalkyl such as cyclopentyl and cyclohexyl. I

Tests to measure the repellency of theabovementioned compounds againstinsects by skin application were conducted by smearing the compound-onthe arms of test personnel, who then thrusttheir arms into cagescontaining insects.

The arms were exposed for -minute intervals 2 at 3 minutes each untilthe first insect bite;

Tests to measure the repellency of fabrics impregnated with theabove-mentioned compounds against insect were conducted by uniformlyimpregnating mercerized cotton hose with the com- Ins e'ct RepellencyInsect -Repellency upon application of impregnated v to ski11 fabricagainst Material k v I V H Anopheles j g quadri 11am aegypti a gm)maculatue i z x a, ESTERS OF l-HYDROXY-CYCLOPENTANE- V CARBOXYLIO ACIDMina. propyl' ester over 60 i-amyl ester over 120 .cyclopentyl ester 23766 ..i cyclohexyl ester 236 39 over 10 days.

I). ESTERS OF l-FYDROXY-CYCLOPENTANE- ACETIC'AOID cyclohexyl ester -e330 50 over 10 days.

" a. ES'IERS OF 1-HYDROXY-CYOLOHEXANE- v OARBOXYLIO ACID V propyl ester.over 60 .r over 60 194 1 over,5 days. 227 43 over 10 days. l 255 46 Do.cyclohexyl ester e 258 78 Do.

d. ESTERS 0F l-HYDROXY-GYOLOHEXANE- ACIE I IO ACID I ethyl cster: 24$ 32over 10 days. propyl ester 238 41 at least 1 day. butyl ester.. 4 255 46over 10 days. i-amyl'ester 212 Do. cyclopentyl ester 271 39 Do.cyclohexyl estcr V 330 50 pound at a rate equivalent to 3.3-gms'. persq. it; I

drawing the dried hose over the arms of test personnel, who then thrusttheir covered arms into cages containing insects for 1 to 2 minutes.

The following table illustrates the results obtained by the above testmethods against A'd'es aegypti and Anopheles quadn'maculatus, asexamples of insects against which the invention is applicable, by usingcompounds in accordance with the present invention:

The esters of 1-hydroxycyclopentaneor I cyclohexanecarboxylic or -aceticacids maybe V reactions:

prepared by either of the following two type 3. By Reformatsky reactionbetween cyclopentanone or cyclohexanone and an ester of bromo-aceticacid in the presence of zinc, benzene, and optionally a catalyst such astoluenesulfonic acid; followed by the introduction of the hydroxyl groupin the 1-position by reacting the product of the Reformatsky reactionwith diluted sulfuric or hydrochloric acid.

The following examples illustrate the preparation of several typicalcompounds enumerated in the above table:

Example 1 A solution of 450 gm. of sodium bisulfite in 900 cc.- of;water is cooled to 10 C.,and 344 gms. (about 4mols). of cyclopentanoneare added slowly and at a rate which does not permit the temperature torise above 15 C. The mixture is again cooled to 10 C. and 200 gms. ofcold sodium cyanide in 800 cc. of water are added slowly, care beingtaken that the temperature does not substantially rise abovel" C. Themixture is then permitted to rise to 20 -C. over av period of 2 hours.Two layers, one of which contains cyanohydrin, form and are separated.800 cc. of concentrated hydrochloric acid are then added to thecyanohydrin containing layer and. I

the mixture is moderately heated in a steam bath overnight, thenfiltered. The residue is triturated 22 gms. of thel-hydroxy-cyclopentanecarbox-- ylic acid obtained by the above reactionare reacted with 31 gms. of cyclopentanol in the presence of 90 gms. ofbenzene and 1.5 gms. of toluenesulfonic acid catalyst. The reactionmixture is heated under reflux for 6 hours and the cyclopentyl ester of1-hydr0xy-cyclopentanecarboxylic acid is obtained as the reactionproduct.

Example 2 The 22 gins. of l-hydroxy-cyclopentanecarboxylicacid obtainedin accordance with the first paragraph of Example '1 and reacted with 40gms. of cyclohexanol in the presence of 90 gms. of benzene and 3 gms. oftoluenesulfonic acid catalyst.

The reaction mixture is heated under reflux for 5 hours. The yield is2'7 gms. of the cyclohexyl ester of l-hydroxy cyclohexanecarboxylicacid, a liquid boiling at 9798 C. at .5 mm. pressure.

Example 3 acetic acid, and a non-toxic insect-repellent adjuvant as acarrier therefor.

147 gms. of cyclohexanone, 1500 cc. of ether and 1129 gms. of sodiumcyanide are placed in a 3 liter flask with good stirring. The mixture iscooled to 0 C., and 200 cc. of concentrated hydrochloric acid, 35%, areadded over a period of 5 hours, corresponding to a rate of addition ofabout 25 drops per minute. The liquid is decanted, and the ether istaken off by heating on a steam cone under reduced pressure. The residueremainingafter the removal of the ether is dissolved in 300 cc. ofconcentrated hydrochloric acid and placed on a steam cone in a 1 literErlenmeyer flask and heated overnight. The resulting ammonium chloridelayer is separated, and the remainder is cooled and the reactionproduct, l-hydroxy-cyclohexanecarboxylic acid, is permitted-tocrystallize. The system is then filtered and 4 the residue extractedwith ether which is then removed and additional crystals arecrystallized with the aid of benzene. The resulting yield is 100 gms. ofwhite crystals of 1-hydroxy-cyclohexanecarboxylic acid. The abovesynthesis is based on a synthesis described by Bucherer in Berichte,vol. 2'7, page 1231 (1894) V 23 gms. of l-hydroxy cyclohexanecarboxylicacid obtained by the above reaction are added to 35 gms. of iso-amylalcohol, 2 gms. of toluenesulfonic acid, and 100 gms. of benzene. Thereaction mixture is heated with refluxing for 6 hours. 24 gms. of theiso-amyl esters of l-hydroxy-cyclohexanecarboxylic acid,aliquidboiling'at 89-90" C. at .5 mm. pressure, are obtained:

Example 4 Cyclohexanone and ethyl bromoacetate are reacted understandard conditions of the Reformatsky reaction (see Berichte, vol. 28,p. 2839) in the presence of zinc and benzene. The resulting intermediateorgano-metallic product is treated With'diluted sulfuric acid. Theresulting product, the ethyl ester of l-hydroxy-cyclohexaneacetic acid,is separated by distillation and is obtained in the form of a liquidhaving a boiling point of 87-88 C. at 2 mm. pressure, with a refractiveindex of n :,1.4650.

For ease of application the compounds contemplatedby -the' presentinvention may be incorporated in a suitable inert liquid or solidcarrier such as mineral oil, alcohol, petrolatum, etc. For facile anduniform fabric impregnation, they may be applied in an inert solvent,such as alcohol, ether, etc.

Having thus described our invention, we claim: 1. An insect repellentcomposition comprising .a member ofs-the group consisting of thecyclohexylesterxof lehydroxy-cyclopentaneacetic acid, 40

the 'cyclohexylzzester of 1-hydroxY-cyclohexanecarboxylic' acid, thecyclopentyl ester of l-hy- 'droxyecyclohexanea'cetic. acid, and the'cycloh'exyl ester of"1-hydroxyecyclohexaneacetic acid; and

a non-toxic insect-repellent adjuvantas a carrier therefor: I I 12; Aninsect" repellent composition comprising the cyclohexylzester "of l-hydroxy cyclopentane- -'acetic acid, and. a non-toxic;insect-repellentadjuvant as a carrier therefor.

' 3.- An insect rep'ellent compositionc'omprising :the "cyclohexyl esterof; '1 hydroxycyclohexanecarboxylic acid, and anon-toxicinsect-repellent ad'juvant'as a carrier therefor.

4. An insect repellent compos-ti'on comprising the cyclopentyl ester ofl-hydroxy-cyclohexane- '5. insect repellent composition comprising the'cyclohex'yl ester of l-hydroxy-cyclohexaneacetic acid, and a non-toxicinsect-repellent adjuvant a's a carrierther'eforj l -6."An-insectrepellent fabric comprising a fabricimpregnated with the cyclohexylester of l-hydroxy cyclopentaneacetic acid.

'-=riciinpregnated with the cyclohex yl' esteroflhydroxy-cyclohexanecarboxylic acid.

I v 7.- An insect repellent fabric comprising a fab- 8. An insectrepellent fabric comprising a fabric impregnated with the cyclopentylester of l- (References on following page) REFERENCES CITED Thefollowing references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Kon et a1.: Dehydration ofBeta-Hydroxy 6 Esters, 1932, Chemical Abstracts, v01. 26, pages 5908 and5909.

OSRDInsect Control Committee Report No. 16, Interim Report No. 0-87,February 1, 1945. Publication date August 1, 1947. 167-OSRD.

Newman et a1.: J. A. C. 8., vol. 68, October 1946, pages 2112-2115.167-12.

Tarbouriech et a1.: Comptes Rendus, vol. 4 pages 604-606 (1909). (Copyin Patent Office Scientific Library.)

McRae et a1.: Syntheses of Succinic Acid, 1943, Chemical Abstracts, Vol.37, pages 4056 and 4057.

1. AN INSECT REPELLENT COMPOSITION COMPRISING A MEMBER OF THE GROUPCONSISTING OF THE CYCLOHEXYL ESTER OF 1-HYDRO-CYCLOPENTANEACETIC ACID,THE CYCLOHEXYL ESTER OF 1-HYDROXY-CYCLOHEXANECARBOXYLIC ACID, THECYCLOPENTYL ESTER OF 1-HYDROXY-CYCLOHEXANEACETIC ACID, AND THECYCLOHEXYL ESTER OF 1-HYDROXY-CYCLOHEXANEACETIC ACID; AND A NON-TOXICINSECT-REPELLENT ADJUVANT AS A CARRIER THEREFOR.